HIF1ɑ-CBX4正反馈调控在肺动脉高压hnRNPs依赖的外泌体miRNAs分拣过程中的作用机制研究

Pulmonary arterial hypertension (PAH) is a severe clinical pulmonary syndrome，the exact mechanism of which is still undefined. In our preliminary study, the exosomal miR-663b, miR-708, and miR-1305 displayed their increasing trend in PAH, involving in both cellular model and the cohort study. Further bioinformatics and investigation revealed that the sumolated hnRNPA2/B1 could be the regulator of exosomal miRNA sorting in PAH. In the other hand, we identified the CBX4 could be the potential upstream of sumolated hnRNPA2/B1, which exerted its activity of SUMOlation ligase (E3). In addition, it is of possibility that there is a positive feedback effect between hypoxic molecular marker HIF-1ɑ and the CBX4, the interaction of which could be the dominant factor for sumolated hnRNPA2/B1-induced exosomal miRNAs sorting in PAH. In the present study, we tend to investigate the hypothesis that HIF-1ɑ-CBX4 feedback effect triggers the CBX4-induced sumolated hnRNPA2/B-dependent sorting of exosomal miRNAs. And it would be an exploration for the mechanism of PAH via exosome and its containing miRNAs. The project will provide the references and new directions for the early protection, diagnosis, clinical evaluation, and therapy of the PAH.

肺动脉高压是一种严重的肺部临床综合征, 其具体发病机制尚不明确。本课题组预实验中发现，外泌体miR-663b、miR-708及miR-1305在肺动脉高压细胞模型及相关人群中均显著上升。生物信息学分析显示上述3种外泌体miRNAs的分拣可能受到苏木化hnRNPA2/B1调控。同时，CBX4也表现出其苏木化连接酶E3作用，参与调控了hnRNPA2/B1的苏木化。此外，缺氧靶标分子HIF-1ɑ与CBX4之间还可能存在正反馈效应，这可能是引起hnRNPA2/B1依赖型miRNAs分拣的主要原因。本研究拟通过人群、细胞及动物实验，探讨HIF-1ɑ-CBX4正反馈机制调控CBX4介导的苏木化hnRNPA2/B1依赖型外泌体miRNAs分拣这一假说，从外泌体miRNAs及其分拣角度阐明肺动脉高压的致病机制。该项目的实施可为今后肺动脉高压早期筛查、预防、诊断及治疗提供新的研究方向及理论依据。

肺动脉高压是一种严重的肺部临床综合征, 其具体发病机制尚不明确。本课题组预实验中发现，外泌体miR-663b、miR-550a及miR-1305在肺动脉高压细胞模型及相关人群中均显著上升。生物信息学分析显示上述3种外泌体miRNAs的分拣可能受到苏木化hnRNPA2/B1调控。同时，CBX4也表现出其苏木化连接酶E3作用，参与调控了hnRNPA2/B1的苏木化。此外，缺氧靶标分子HIF-1ɑ与CBX4之间还可能存在正反馈效应，这可能是引起hnRNPA2/B1依赖型miRNAs分拣的主要原因。本研究拟通过人群、细胞及动物实验，探讨HIF-1ɑ-CBX4正反馈机制调控CBX4介导的苏木化hnRNPA2/B1依赖型外泌体miRNAs分拣这一假说，从外泌体miRNAs及其分拣角度阐明肺动脉高压的致病机制。该项目的实施可为今后肺动脉高压早期筛查、预防、诊断及治疗提供新的研究方向及理论依据。